Cell Growth & Differentiation, Vol 8, Issue 2 179-186, Copyright © 1997 by American Association of Cancer Research

ARTICLES

Transactivation through Ets and Ap1 transcription sites determines the expression of the tumor-suppressing gene maspin

M Zhang, N Maass, D Magit and R Sager
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Tumor invasion and metastasis are processes poorly understood at the molecular level. Maspin is a serine protease inhibitor (serpin) with tumor-suppressing function in the mammary gland. Maspin gene expression is decreased with malignancy and is lost in metastatic cells. We show in this report that differential expression of maspin in normal and carcinoma-derived mammary epithelial cells is regulated at the transcriptional level. We have identified the Ets and Ap1 sites in the maspin promoter that are active in regulating maspin expression in normal mammary epithelial cells but inactive in tumor cells. The Ets site alone is sufficient to activate transcription in a heterologous promoter, whereas the Ap1 site cooperates with Ets in activation. The enhancing function by Ets and Ap1 elements is decreased in primary tumor cells (21NT) and is abolished in invasive tumor cells (MDA-231). Thus, loss of maspin expression during tumor progression results at least in part from the absence of transactivation through the Ets and Ap1 sites.

This article has been cited by other articles:

				T. Yokota, T. Bui, Y. Liu, M. Yi, K. K. Hunt, and K. Keyomarsi Differential Regulation of Elafin in Normal and Tumor-Derived Mammary Epithelial Cells Is Mediated by CCAAT/Enhancer Binding Protein Cancer Res., December 1, 2007; 67(23): 11272 - 11283. [Abstract] [Full Text] [PDF]

				S. E. Wang, A. Narasanna, C. W. Whitell, F. Y. Wu, D. B. Friedman, and C. L. Arteaga Convergence of p53 and Transforming Growth Factor beta (TGFbeta) Signaling on Activating Expression of the Tumor Suppressor Gene maspin in Mammary Epithelial Cells J. Biol. Chem., February 23, 2007; 282(8): 5661 - 5669. [Abstract] [Full Text] [PDF]

				I. Nazarenko, G. Kristiansen, S. Fonfara, R. Guenther, C. Gieseler, W. Kemmner, R. Schafer, I. Petersen, and C. Sers H-REV107-1 Stimulates Growth in Non-Small Cell Lung Carcinomas via the Activation of Mitogenic Signaling Am. J. Pathol., October 1, 2006; 169(4): 1427 - 1439. [Abstract] [Full Text] [PDF]

				K. Latha, W. Zhang, N. Cella, H. Y. Shi, and M. Zhang Maspin Mediates Increased Tumor Cell Apoptosis upon Induction of the Mitochondrial Permeability Transition Mol. Cell. Biol., March 1, 2005; 25(5): 1737 - 1748. [Abstract] [Full Text] [PDF]

				K. Hirai, K. Koizumi, S. Haraguchi, T. Hirata, I. Mikami, M. Fukushima, S. Yamagishi, T. Kawashima, D. Okada, K. Shimizu, et al. Prognostic Significance of the Tumor Suppressor Gene Maspin in Non-Small Cell Lung Cancer Ann. Thorac. Surg., January 1, 2005; 79(1): 248 - 253. [Abstract] [Full Text] [PDF]

				S. Kim, J. Han, J. Kim, and C. Park Maspin Expression Is Transactivated by p63 and Is Critical for the Modulation of Lung Cancer Progression Cancer Res., October 1, 2004; 64(19): 6900 - 6905. [Abstract] [Full Text] [PDF]

				F. Gao, H. Y. Shi, C. Daughty, N. Cella, and M. Zhang Maspin plays an essential role in early embryonic development Development, April 1, 2004; 131(7): 1479 - 1489. [Abstract] [Full Text] [PDF]

				C. K. Galang, W. J. Muller, G. Foos, R. G. Oshima, and C. A. Hauser Changes in the Expression of Many Ets Family Transcription Factors and of Potential Target Genes in Normal Mammary Tissue and Tumors J. Biol. Chem., March 19, 2004; 279(12): 11281 - 11292. [Abstract] [Full Text] [PDF]

				Z. Khalkhali-Ellis, A. L. Christian, D. A. Kirschmann, E. M. Edwards, M. Rezaie-Thompson, M. A. Vasef, L. M. Gruman, R. E. B. Seftor, L. E. Norwood, and M. J. C. Hendrix Regulating the Tumor Suppressor Gene Maspin in Breast Cancer Cells: A Potential Mechanism for the Anticancer Properties of Tamoxifen Clin. Cancer Res., January 15, 2004; 10(2): 449 - 454. [Abstract] [Full Text] [PDF]

				Y. Akiyama, C. Maesawa, S. Ogasawara, M. Terashima, and T. Masuda Cell-Type-Specific Repression of the Maspin Gene Is Disrupted Frequently by Demethylation at the Promoter Region in Gastric Intestinal Metaplasia and Cancer Cells Am. J. Pathol., November 1, 2003; 163(5): 1911 - 1919. [Abstract] [Full Text] [PDF]

				R. J. Feldman, V. I. Sementchenko, M. Gayed, M. M. Fraig, and D. K. Watson Pdef Expression in Human Breast Cancer Is Correlated with Invasive Potential and Altered Gene Expression Cancer Res., August 1, 2003; 63(15): 4626 - 4631. [Abstract] [Full Text] [PDF]

				D. Ghosh, T. Ezashi, M. C. Ostrowski, and R. M. Roberts A Central Role for Ets-2 in the Transcriptional Regulation and Cyclic Adenosine 5'-Monophosphate Responsiveness of the Human Chorionic Gonadotropin-{beta} Subunit Gene Mol. Endocrinol., January 1, 2003; 17(1): 11 - 26. [Abstract] [Full Text] [PDF]

				A. K. Sood, M. S. Fletcher, L. M. Gruman, J. E. Coffin, S. Jabbari, Z. Khalkhali-Ellis, N. Arbour, E. A. Seftor, and M. J. C. Hendrix The Paradoxical Expression of Maspin in Ovarian Carcinoma Clin. Cancer Res., September 1, 2002; 8(9): 2924 - 2932. [Abstract] [Full Text] [PDF]

				Z. Zou, W. Zhang, D. Young, M. G. Gleave, P. Rennie, T. Connell, R. Connelly, J. Moul, S. Srivastava, and I. Sesterhenn Maspin Expression Profile in Human Prostate Cancer (CaP) and in Vitro Induction of Maspin Expression by Androgen Ablation Clin. Cancer Res., May 1, 2002; 8(5): 1172 - 1177. [Abstract] [Full Text] [PDF]

				H. Y Shi, W. Zhang, R. Liang, S. Abraham, F. S. Kittrell, D. Medina, and M. Zhang Blocking Tumor Growth, Invasion, and Metastasis by Maspin in a Syngeneic Breast Cancer Model Cancer Res., September 1, 2001; 61(18): 6945 - 6951. [Abstract] [Full Text] [PDF]

				N. Maass, T. Hojo, M. Ueding, J. Lüttges, G. Klöppel, W. Jonat, and K. Nagasaki Expression of the Tumor Suppressor Gene Maspin in Human Pancreatic Cancers Clin. Cancer Res., April 1, 2001; 7(4): 812 - 817. [Abstract] [Full Text]

				Z. Zou, C. Gao, A. K. Nagaich, T. Connell, S.'i. Saito, J. W. Moul, P. Seth, E. Appella, and S. Srivastava p53 Regulates the Expression of the Tumor Suppressor Gene Maspin J. Biol. Chem., February 25, 2000; 275(9): 6051 - 6054. [Abstract] [Full Text] [PDF]

				S. G. Blumenthal, G. Aichele, T. Wirth, A. P. Czernilofsky, A. Nordheim, and J. Dittmer Regulation of the Human Interleukin-5 Promoter by Ets Transcription Factors. ETS1 AND ETS2, BUT NOT ELF-1, COOPERATE WITH GATA3 AND HTLV-I TAX1 J. Biol. Chem., April 30, 1999; 274(18): 12910 - 12916. [Abstract] [Full Text] [PDF]

				A. S. Takaoka, T. Yamada, M. Gotoh, Y. Kanai, K. Imai, and S. Hirohashi Cloning and Characterization of the Human beta 4-Integrin Gene Promoter and Enhancers J. Biol. Chem., December 11, 1998; 273(50): 33848 - 33855. [Abstract] [Full Text] [PDF]

				V. K. Harris, E. D. E. Liaudet-Coopman, B. J. Boyle, A. Wellstein, and A. T. Riegel Phorbol Ester-induced Transcription of a Fibroblast Growth Factor-binding Protein Is Modulated by a Complex Interplay of Positive and Negative Regulatory Promoter Elements J. Biol. Chem., July 24, 1998; 273(30): 19130 - 19139. [Abstract] [Full Text] [PDF]

				M. Zhang, D. Magit, and R. Sager Expression of maspin in prostate cells is regulated by a positive Ets element and a negative hormonal responsive element site recognized by androgen receptor PNAS, May 27, 1997; 94(11): 5673 - 5678. [Abstract] [Full Text] [PDF]

				A. Tugores, J. Le, I. Sorokina, A. J. Snijders, M. Duyao, P. S. Reddy, L. Carlee, M. Ronshaugen, A. Mushegian, T. Watanaskul, et al. The Epithelium-specific ETS Protein EHF/ESE-3 Is a Context-dependent Transcriptional Repressor Downstream of MAPK Signaling Cascades J. Biol. Chem., June 1, 2001; 276(23): 20397 - 20406. [Abstract] [Full Text] [PDF]